8978 J . Org. Chem., Vol. 61, No. 25, 1996
Favino et al.
ments were performed by using the first quadrupole for mass
selection, the second as collision cell (Ar, p ) 0.8 Torr), and
the third as mass analyzer. The samples were prepared by
dissolving into the matrix (3-mercapto-1,2-propandiol) com-
mercial â-cyclodextrin and a CH2Cl2 solution of the acylpyr-
roline.
evaporation of the dried organic phase (90 g) was dissolved in
dry ethanol and added to a 1 M solution of dry ammonia in
EtOH (500 mL). After 2 h, the TLC analysis indicated the
complete consumption of the starting material. The volume
of the reaction mixture was reduced upon evaporation under
vacuum in the cold. The oily material was taken up in 200
mL of CH2Cl2 and washed with dilute NaOH and water. The
residue obtained upon evaporation of the solvent was distilled
at 150 mmHg at 100 °C to provide 8, oil, 11 g (55%). 1H NMR
(CDCl3), δ: 1.35 (s broad, 2H), 1.60 (m, 2H), 1.78 (t, 3H, J )
2.0), 2.20 (m, 2H), 2.80 (t, 2H, J ) 7.0).
4-Hexyn -1-ol (17). Bromine (47 g, 0.298 mol) was added
dropwise under stirring at 0 °C to a solution of 4-hexen-1-ol
(16) (29.8 g, 0.298 mol) in CH2Cl2 (250 mL). The reaction
mixture was kept for 2 h at rt and then evaporated under
reduced pressure. The oily residue, 90 g, in EtOH (100 mL)
was added slowly to a stirred solution of KOH (100 g, 1.6 mol)
in EtOH (300 mL), and the reaction mixture was refluxed for
16 h. Concentrated HCl was then added at 0 °C to neutrality.
The separated solid was filtered and washed with some ether.
The organic phase was concentrated to a small volume, diluted
with ice-water, and extracted with Et2O (3 × 100 mL). The
dried organic phase was carefully concentrated. Vacuum
distillation (90 °C, water pump) of the residue afforded 17, 23
g (79%). 1H NMR (CDCl3), δ: 1.65 (m, 2H), 1.75 (s, 1H), 2.13
(q, 2H, J ) 7.0), 2.22 (s, 3H), 3.65 (q, 2H, J ) 7.0). Anal. Calcd
for C6H10O: C, 73.43; H, 10.27. Found: C, 73.47; H, 10.25.
4-Hexen oic Acid Am id e (19). 3-Buten-2-ol (18) (200 mL,
2.32 mol), triethyl orthoacetate (426 mL, 2.32 mol), and acetic
acid (7 mL) were refluxed for 32 h. The mixture was submitted
to distillation discarding the 75-100 °C fraction and, subse-
quently, collecting the fraction boiling at 70-80 °C at 30
mmHg, 240 g, shown to be a ca. 65:35 mixture of ethyl
4-hexenoate and unreacted triethyl orthoacetate. The crude
mixture in 250 mL of EtOH was refluxed 2 h with 680 mL of
10% NaOH. The reaction mixture was concentrated under
reduced pressure and acidified with cold concd HCl while
stirring with 250 mL of Et2O. The aqueous phase was further
extracted with ether. Evaporation of the organic extracts left
a residue of 4-hexenoic acid, 164 g (62%). 1H NMR (CDCl3),
δ: 1.65 (d, 3H, J ) 6.3), 2.30-2.45 (m, 4H), 5.45 (m, 2H), 10.9
(s broad, 1H). The latter material neat was added dropwise
under stirring to SOCl2 (171 g, 1.44 mol), and the reaction
mixture was refluxed for 4 h. The reaction mixture was
submitted to vacuum distillation (40 mmHg) collecting at 85
°C the desired chloride, 137 g (72%). The latter product in
THF (100 mL) was added dropwise to stirred 33% aqueous
ammonia (500 mL). After 4 h the reaction mixture was
extracted with Et2O (3 × 150 mL). On crystallization from
hexane of the residue obtained by evaporation of the dried
organic phase was obtained the amide 19, mp 98-100 °C, 97.5
g (86%). 1H NMR (CDCl3), δ: 1.65 (d, 3H, J ) 6.2), 2.30 (m,
4H), 5.5 (m, 2H), 5.70 (s broad, 1H), 6.10 (s broad, 1H). Anal.
Calcd for C6H11NO: C, 63.68; H, 9.80. Found: C, 63.60; H,
9.78.
1-Am in oh ex-4-en e (20). The amide 19 (52.5 g, 0.46 mol)
in THF (100 mL) was added dropwise to a refluxing mixture
of LiAlH4 (28 g, 0.75 mol) in 300 mL of THF. After 6 h the
reaction mixture was treated with AcOEt (500 mL) and a
saturated solution of Na,K tartrate (150 mL). The dried
organic phase was carefully evaporated to oily 20, 23 g (50%).
1H NMR (CDCl3), δ: 1.2 (s, 2H), 1.5 (m, 2H), 1.65 (d, 3H, J )
6.5), 2.05 (m, 2H), 2.65 (t, 2H, J ) 6.7), 5.4 (m, 2H). A solution
of 20 (20 g, 0.2 mol) in CH2Cl2 (100 mL) was then treated at
0 °C with Ac2O (40 mL) and pyridine (40 mL). After standing
overnight, the reaction mixture was concentrated and the
residue was partitioned between CH2Cl2 (200 mL) and ice-
water. The organic phase was washed with NaHCO3 solution,
dilute HCl, and water. The residue obtained upon evaporation
of the solvent was chromatographed on SiO2 with hexane-
AcOEt (55:45) to provide the acetyl derivative of the amine
20 (28.8 g, 88%), oil. 1H NMR (CDCl3), δ: 1.20 (s broad, 2H),
1.50 (m, 2H), 1.65 (d, 3H, J ) 7.0), 2.05 (s, 3H), 2.70 (t, 2H, J
) 7.1), 3.2 (q, 2H, J ) 7.1), 5.35 (m, 2H). Anal. Calcd for
C8H15ON: C, 68.04; H, 10.71. Found: C, 68.14; H, 10.66.
1-Am in oh ex-4-yn e (8). Meth od A. To a stirred mixture
of 4-hexyn-1-ol (17) (20 g, 0.204 mol) and Et3N (31 mL, 0.226
mol) in CH2Cl2 (200 mL) was added 4-nitrobenzenesulfonyl
chloride (50 g, 0.226 mol) in CH2Cl2 (100 mL) dropwise. After
24 h at rt, the reaction mixture was washed with water, dilute
HCl, and NaHCO3 solution. The residue obtained upon
Meth od B. To a stirred mixture of the acetyl derivative of
1-aminohex-4-ene (20) (see above) (36.9 g, 0.262 mol) in CH2Cl2
(150 mL) was added bromine (13.5 mL, 0.262 mol). After 2 h,
the reaction mixture was concentrated, and the residue in
EtOH was added to a stirred solution of KOH (40 g, 0.73 mol)
in EtOH (200 mL). After 20 h reflux, the reaction mixture
was concentrated under vacuum to a small volume at low
temperature, diluted with water (150 mL), and extracted with
CH2Cl2 (3 × 50 mL). Careful evaporation of the dried organic
phase afforded an oily residue, providing upon distillation at
150 mmHg at 100 °C the desired amine 8, 13 g (51%).
Nitr ile of Hep t-4-en oic Acid (22). cis-3-Hexen-1-ol (21)
(100 g, 1 mol) in CH2Cl2 (1 L) at 0 °C was treated under stirring
portionwise with Ph3P (262 g, 1 mol) and NBS (178 g, 1 mol),
keeping the temperature below 10 °C. After 20 h at rt, most
of the solvent was evaporated, Et2O/hexane 1:1 (500 mL) was
added, and after standing overnight in the refrigerator, the
precipitate was removed by filtration. The residue obtained
upon evaporation of the organic phase was chromatographed
on SiO2 with CH2Cl2 to provide 1-bromohex-3-ene, oil, 120 g
(73%). 1H NMR (CDCl3), δ: 0.95 (t, 3H, J ) 7.0), 2.6 (q, 2H,
J ) 7.0), 3.35 (t, 2H, J ) 7.5), 5.3 (m, 1H), 5.55 (m, 1H). A
solution of the latter bromide (15 g, 92 mmol) in MeOH (30
mL) was added to NaCN (6.8 g, 130 mmol) in 30% aqueous
methanol (100 mL). After 24 h, the reaction mixture was
concentrated, diluted with ice-water, and extracted with Et2O
(2 × 50 mL). The residue obtained upon evaporation of the
solvent afforded upon distillation (75 °C, 40 mmHg) the nitrile
22 , oil, 6.3 g (63%). 1H NMR (CDCl3), δ: 0.97 (t, 3H, J )
7.5), 2.1 (m, 2H), 2.35 (q, 2H, J ) 7.5), 3.65 (t, 2H, J ) 6.9),
5.32 (m, 1H), 5.57 (m, 1H). Anal. Calcd for C7H11N: C, 77.01;
H, 10.16. Found: C, 77.09; H, 10.26.
1-Am in oh ep t-4-en e (23). Meth od A. To LiAlH4 (7.2 g,
0.2 mol) in Et2O (150 mL) at -20 °C under stirring in N2
atmosphere was added concd H2SO4 (10 g, 0.1 mol) during 3
h. To the resulting mixture was added dropwise the nitrile
22 (5.4 g, 0.05 mol), and the stirring was continued for 14 h.
To the reaction mixture was added a small quantity of EtOH,
followed by 10% NaOH (150 mL). Vacuum distillation (70-
80 °C, water pump) of the organic residue affords the amine
23. The material was contaminated by a few minor compo-
nents which could not be separated. Thus the crude mixture
was treated with Ac2O, 10.2 g (0.1 mol), and pyridine, 8 g (0.1
mol), at rt for 16 h in CH2Cl2 (150 mL). The organic phase
was treated with ice-water and washed with 3% NaHCO3,
0.1 N HCl, and water. The residue obtained upon evaporation
of the dried solution was chromatographed on SiO2 with
hexane-AcOEt (6:4) to provide 1-(N-acetylamino)hept-4-ene
(4.7 g, 60%), oil. 1H NMR (CDCl3), δ: 0.95 (t, 3H, J ) 7.5),
1.6 (m, 2H), 2.0 (s, 3H), 2.05 (m, 2H), 3.25 (q, 2H, J ) 7.5), 5.3
(m, 2H), 5.9 (s broad, 1H). Anal. Calcd for C9H17NO: C, 69.63;
H, 11.04. Found: C, 69.74; H, 10.96.
Meth od B. A Grignard reagent was prepared in THF (350
mL) from 1-bromo-cis-3-hexene (98 g, 0.6 mol) and Mg turnings
(14.5 g, 0.6 mol). The consumption of Mg took place rapidly
at gentle reflux. The resulting mixture was added dropwise
to a large excess of solid CO2 in THF (300 mL). After 2 h, an
excess of cold concd HCl was added, and the mixture was
concentrated to a small volume and then partitioned between
water and Et2O. The desired cis-4-heptenoic acid (24) was
obtained in 83% yield upon extraction from the ether layer
with 30% NaOH, acidification of the aqueous phase, and back
extraction with Et2O. 1H NMR (CDCl3), δ: 0.95 (t, 3H, J )
7.5), 2.05 (m, 2H), 2.4 (m, 4H), 5.30-5.55 (m, 2H). Product
24 (60 g, 0.47 mol) was added dropwise to SOCl2 (41 mL, 0.55